Declines in immune function are well described in the elderly, and are considered to be significant contributors to disease burden in this population. In particular, age-related declines in T cell function appear to be associated with an increased risk and severity of infection, impaired responses to vaccination, and poorer control of cancer. Moreover, reactivation of latent infections is a common consequence of waning immunological function in the elderly. Regulatory T cells (or Treg), a specialized subset of CD4+ T cells, have recently been shown to control the intensity of immune responses, both in rodents and humans. This subset of T cells constitutively express CD25, cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the TNF receptor family member GITR. These cells also express FoxPS, a transcription factor from the forkhead family, which constitutes the most definite marker of Treg activity in humans. We have demonstrated that these cells are responsible for the establishment and maintenance of latent infection with the parasite Leishmania major in the tissues of its host. Our preliminary data indicate that Treg numbers increase dramatically with age in the mouse, correlating with spontaneous reactivation of L. major infection in aged mice. Moreover, T cell levels of FoxPS mRNA and percentages of CD4+ cells expressing CTLA-4 or GITR are also increased in aged human donors (>70 yrs old), compared with young donors (<30 yrs old). These results suggest a novel mechanism for T cell immune dysfunction in aging hosts in which altered Treg dynamics leads to suppression of efficient effector and memory responses, and disease reactivation. Finally, while Treg clearly modulate antigen-presenting cell (ARC) and T cell effector function, the activation levels of ARC and/or effector T cells are important regulators of Treg-mediated suppression. Costimulation through either CD40 or GITR signaling, which act on the ARC and the effector T cells respectively, abolishes Treg-mediated suppression. Such costimulation might thus be used to reverse deleterious Treg activity in the elderly. The long-term goal of this research is to uncover molecular mechanisms for manipulating Treg function in order to devise novel therapeutic approaches to enhance immune control of infections and vaccine efficacy in the elderly. The goal of this application is to define the mechanisms and consequences of Treg accumulation in aging hosts. Our hypotheses are that: (1) age-dependent accumulation of Treg occurs in lymphoid organs and peripheral tissues; (2) Treg accumulation contributes to systemic and local immune suppression in aging hosts; and (3) CD40 and GITR signaling can reverse Treg-mediated suppression. To test these hypotheses, we will determine: (a) the extent of Treg accumulation in the elderly; (b) what the functional consequences of such accumulation are; and (c) whether increased costimulation can override Treg function in the elderly.